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Neurodegenerative disease

Tau immunotherapy targets transcellular propagation

Nature Reviews Drug Discovery volume 12, page 904 (2013)Cite this article

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Tau aggregates are observed in a number of neurodegenerative diseases (referred to as tauopathies) and lead to the formation of neurofibrillary tangles that are associated with synaptic dysfunction and cognitive decline. Previous studies have suggested that tau fibrils can be released into the extracellular space and induce aggregation of tau in recipient cells through a process referred to as seeding. On the one hand, this promotes propagation of the pathology but on the other hand it offers an opportunity to target extracellular tau and disrupt the process.

Yanamandra et al. used a cell-based biosensor assay to screen for tau-specific monoclonal antibodies that block tau aggregation induced by the addition of brain lysates from transgenic mice expressing human P301S tau — a mutated form of tau that causes inherited frontotemporal dementia. They selected three effective antibodies with different potencies (HJ8.5, HJ9.3 and HJ9.4) and confirmed their ability to block the seeding activity of P301S tau aggregates in HEK293 cells using a fluorescence resonance energy transfer (FRET) assay. As the antibodies were not detected inside the cells, the authors suggest that their mechanism of action could involve blocking the cellular uptake of seeding competent forms of tau.

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References

  1. Yanamandra, K. et al. Anti-tau antibodies that block tau aggregate seeding in vitro markedly decrease pathology and improve cognition in vivo. Neuron 80, 402–414 (2013)

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  1. Monica Hoyos Flight
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Flight, M. Tau immunotherapy targets transcellular propagation. Nat Rev Drug Discov 12, 904 (2013). https://doi.org/10.1038/nrd4179

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